1. Calcium Signals Laboratory, Departments of Biomedical Engineering and Neuroscience, The Johns Hopkins University School of Medicine, Ross Building, Room 713, 720 Rutland Avenue, Baltimore, Maryland 21205, USA
2. These authors contributed equally to this work.

Correspondence to: David T. Yue¹ Correspondence and requests for materials should be addressed to D.T.Y. (Email: dyue@bme.jhu.edu).

Abstract

Ca²⁺/calmodulin-dependent regulation of voltage-gated Ca_V1–2 Ca²⁺ channels shows extraordinary modes of spatial Ca²⁺ decoding and channel modulation^{1, 2, 3, 4, 5, 6}, vital for many biological functions^{6, 7, 8, 9}. A single calmodulin (CaM) molecule associates constitutively with the channel's carboxy-terminal tail^{3, 10, 11, 12, 13}, and Ca²⁺ binding to the C-terminal and N-terminal lobes of CaM can each induce distinct channel regulations^{2, 14}. As expected from close channel proximity, the C-lobe responds to the roughly 100-M Ca²⁺ pulses driven by the associated channel^{15, 16}, a behaviour defined as 'local Ca²⁺ selectivity'. Conversely, all previous observations have indicated that the N-lobe somehow senses the far weaker signals from distant Ca²⁺ sources^{2, 3, 17, 18}. This 'global Ca²⁺ selectivity' satisfies a general signalling requirement, enabling a resident molecule to remotely sense cellular Ca²⁺ activity, which would otherwise be overshadowed by Ca²⁺ entry through the host channel^{5, 6}. Here we show that the spatial Ca²⁺ selectivity of N-lobe CaM regulation is not invariably global but can be switched by a novel Ca²⁺/CaM-binding site within the amino terminus of channels (NSCaTE, for N-terminal spatial Ca²⁺ transforming element). Native Ca_V2.2 channels lack this element and show N-lobe regulation with a global selectivity. On the introduction of NSCaTE into these channels, spatial Ca²⁺ selectivity transforms from a global to local profile. Given this effect, we examined Ca_V1.2/Ca_V1.3 channels, which naturally contain NSCaTE, and found that their N-lobe selectivity is indeed local. Disruption of this element produces a global selectivity, confirming the native function of NSCaTE. Thus, differences in spatial selectivity between advanced Ca_V1 and Ca_V2 channel isoforms are explained by the presence or absence of NSCaTE. Beyond functional effects, the position of NSCaTE on the channel's amino terminus indicates that CaM can bridge the amino terminus and carboxy terminus of channels. Finally, the modularity of NSCaTE offers practical means for understanding the basis of global Ca²⁺ selectivity¹⁹.

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